Westra W H, Offerhaus G J, Goodman S N, Slebos R J, Polak M, Baas I O, Rodenhuis S, Hruban R H
Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland.
Am J Surg Pathol. 1993 Mar;17(3):213-20. doi: 10.1097/00000478-199303000-00001.
Mutations in the p53 tumor suppressor gene are frequently observed in primary lung adenocarcinomas, suggesting that these mutations are critical events in the malignant transformation of airway cells. These mutations are often associated with stabilization of the p53 gene product, resulting in the accumulation of p53 protein. In this study, 70 formalin-fixed, paraffin-embedded primary lung adenocarcinomas resected for potential cure were examined for p53 overexpression. These 70 lung adenocarcinomas were obtained from a series of patients with well-documented clinical histories, and all 70 carcinomas had been previously evaluated for point mutations in codon 12 of the K-ras oncogene. Overexpression of the p53 protein was detected using an antigen retrieval system (Target Unmasking Fluid) and the anti-p53 antibody CM-1. CM-1 is a polyclonal antibody directed against the wild-type p53 protein. Overexpression of the p53 protein was found in 23 (33%) of the 70 lung adenocarcinomas. In all 23 cases, overexpression was confined to neoplastic cells. Overexpression of the p53 protein correlated with cigarette smoking: 10 (56%) of the 18 adenocarcinomas from patients who were current smokers overexpressed p53 compared with 13 (33%) of the 40 adenocarcinomas from patients who had quit smoking and 0 (0%) of the 12 adenocarcinomas from patients who had never smoked (p = 0.002, trend test). Overexpression of the p53 protein was also related to the degree of histologic differentiation: 48% of the p53 negative carcinomas were well differentiated, whereas only 13% (p = 0.003) of the carcinomas in which p53 was overexpressed were well differentiated. Overexpression of the p53 protein did not correlate with point mutations in codon 12 of the K-ras oncogene, nor did it correlate with tumor stage or patient survival. These findings indicate that p53 protein is frequently overexpressed in primary lung adenocarcinomas. Furthermore, the association of tobacco smoking with this overexpression suggests that the p53 gene is a target of specific mutagens in tobacco smoke.
p53肿瘤抑制基因的突变在原发性肺腺癌中经常被观察到，这表明这些突变是气道细胞恶性转化中的关键事件。这些突变通常与p53基因产物的稳定化相关，导致p53蛋白的积累。在本研究中，对70例因潜在治愈目的而切除的福尔马林固定、石蜡包埋的原发性肺腺癌进行了p53过表达检测。这70例肺腺癌来自一系列临床病史记录完善的患者，并且所有70例癌之前都已对K-ras癌基因第12密码子的点突变进行了评估。使用抗原修复系统（目标脱掩液）和抗p53抗体CM-1检测p53蛋白的过表达。CM-1是一种针对野生型p53蛋白的多克隆抗体。在70例肺腺癌中有23例（33%）发现p53蛋白过表达。在所有23例病例中，过表达仅限于肿瘤细胞。p53蛋白过表达与吸烟相关：当前吸烟者的18例腺癌中有10例（56%）p53过表达，相比之下，已戒烟者的40例腺癌中有13例（33%），从不吸烟者的12例腺癌中有0例（0%）（趋势检验，p = 0.002）。p53蛋白过表达也与组织学分化程度相关：p53阴性的癌中有48%为高分化，而p53过表达的癌中只有13%（p = 0.003）为高分化。p53蛋白过表达与K-ras癌基因第12密码子的点突变无关，也与肿瘤分期或患者生存率无关。这些发现表明p53蛋白在原发性肺腺癌中经常过表达。此外，吸烟与这种过表达的关联表明p53基因是烟草烟雾中特定诱变剂的作用靶点。
